The standard approach for treating metastatic prostate cancer (PC) is androgen deprivation (ADT). ADT is also used to treat men relapsing after primary local therapies and, in combination with radiation, men with locally advanced disease. Although highly effective, ADT invariably fails over time. After patients fail ADT, i.e. once they develop castration resistant prostate cancer (CRPC), therapeutic options are limited. Chemotherapy has provided limited benefit in metastatic CRPC patients, and no effective second-line therapies exist after first line docetaxel chemotherapy. Thus, there is an urgent need to develop more effective treatments for PC. The past two decades have seen a major change in cancer treatment paradigms. Anti-cancer agents are no longer being developed based on empiricism, but are now being aimed to inhibit validated targets that are relatively specific for tumor cells. In PC, however, there is a paucity of novel, targeted drugs;in fact, other than anti- androgens, targeted therapies are essentially non-existent in this disease. Pre-clinical models suggest that androgen-sensitive (AS) and androgen-independent (AI) PC cells may be present from the very outset and/or AI cancer cells are selected from AS cells during the course of ADT. Since ADT targets AS cancer cells, it is destined to fail. Thus, for optimal disease control, both AS and AI cells need to be targeted effectively. Under the auspices of the ongoing Merit Review Award, consistent with our original hypothesis, we have determined that sequential treatment of docetaxel followed by ADT provides the best outcomes in xenograft models bearing androgen-sensitive PC cells. However, even the most optimal chemohormone treatments fail over time in this model, suggesting that other targets need to be integrated with chemohormone therapy to enhance outcomes. Other studies in our laboratory with the transgenic TRAMP model have evaluated the effects of ADT and docetaxel with respect to anti-tumor activity and neuroendocrine differentiation. In addition, our initial in vitro studies demonstrate recruitment of ERK- and/or Akt-dependent pathways in PC cells under certain conditions of androgen deprivation and taxane exposure. Finally, angiogenesis appears to be activated soon after ADT in LNCaP xenografts. Taken together, these studies provide additional potential targets for therapeutic intervention. Our aim in the renewal application is to build on this work and study systematically the mechanisms underlying the recruitment of ERK- and Akt-dependent pathways under conditions of ADT, androgen resistance, docetaxel treatment and docetaxel resistance in human PC cells in vitro, and to evaluate the effects of specific inhibitors of these pathways as single agents and in certain combinations with ADT and docetaxel. We will extend this work to in vivo xenograft models, with the goal to optimize anti-tumor activity, particularly of the sequential chemo-hormone therapy backbone. We believe a strength of this proposal is that it has direct clinical relevance, which is underscored by the fact that our previous pre-clinical studies have been successfully translated to two clinical trials in men with hormone sensitive recurrent PC. PUBLIC HEALTH RELEVANCE: The leading cancer in men in the U.S. is prostate cancer. It is also a leading cancer in our aging Veteran population. To date, there are no curative treatments for advanced stages of prostate cancer, including recurrent and metastatic disease. Although hormone therapy and chemotherapy can palliate prostate cancer, they are generally not curative. This proposal will analyze systematically how to improve the treatment of prostate cancer by targeting additional pathways activated in this disease in specific combinations with chemotherapy and hormone therapy. Both cell culture and mouse models will be used. These studies will provide novel information on how to develop more effective treatment regimens for prostate cancer. Thus, the proposal is highly relevant to the healthcare mission of the Department of Veterans Affairs as well as the healthcare of the general population.